Integrated bio-reactor monitor and control system

ABSTRACT

Systems and methods for automatically controlling conditions of a process are disclosed. In one example, a controller is programmed with a sequence of steps and parameters required to carry out a bioreactor process. The controller receives information related to a condition of the process over a first communication network, determines a control signal based on the received information and the programmed process, and sends the control signal over a second communication network to a benchtop utility tower. In one example, the utility tower can include transmitters for temperature, pH, and dissolved oxygen that send information related to a condition of the process to the controller over the first communication network, and an agitation system, a gas control system, a temperature control system and a pump control system that perform a control action based on the control signal affecting the process condition. The utility tower can include a computer with a human-machine interface that communicates with the controller over a third communication network.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/250,415, filed Oct. 13, 2008, which is a divisional of U.S.application Ser. No. 10/723,168, filed Nov. 26, 2003, now U.S. Pat. No.7,435,581, issued Oct. 14, 2008, entitled INTEGRATED BIO-REACTOR MONITORAND CONTROL SYSTEM, each of which is incorporated herein by reference inits entirety. This application is related to U.S. application Ser. No.11/057,079, filed Feb. 10, 2005, now U.S. Pat. No. 7,635,586, issuedDec. 22, 2009.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to systems and methods for managing processconditions in a container or chamber, including controlling bioreactorsfor cell cultures and microbial fermentation, semiconductor fabricationand liquid chromatography.

2. Description of the Related Art

Many manufacturing and biological generation processes consist of acomplex sequence of steps and require positive control overenvironmental conditions to consistently reproduce a desired result. Incell culture growth, for example, geneticists manipulate DNA byidentifying, excise, move and place genes into a variety of cells thatare genetically quite different from the source cell, and theserecombinant cells can produce proteins that may be of immense commercialvalue. Once the gene is successfully transferred to another cell, thegrowth process for the cell must be closely monitored and controlled toprovide an effective environment that promotes cell viability.Understanding and documenting environmental conditions affecting theviability of cells, and accurately controlling such conditions allowsconsistent reproduction of the cell culture process.

Cell culture processes are commonly developed and optimized in abenchtop scaled bioreactor, and then be scaled-up to a large productionprocess according to commercial demands. The process may take weeks oreven months, and include numerous changes to the conditions of themedia, or solution, contained in the bioreactor during this period. Forexample, desired conditional changes to the solution can includeadjustments to pH, temperature, and dissolved oxygen. Providing preciseamounts of certain fluids or gasses to the bioreactor, either directlyor indirectly (e.g., using fluids to heat or cool a solution) changesthese and other conditions of the solution. Typically, monitoring aprocess is accomplished by entering data from a bioreactor sensor into alogbook, from time-to-time. Agitating the solution, or adding fluids orgasses to the solution, is also generally done manually in an amountestimated by the attending operator, and recorded in a paper logbook.Poor documentation and/or imprecisely adding fluid or gas to the processcan result in an unacceptably high level of uncertainty as to the stepsrequired for the process, thereby making a faithful reproduction of theprocess nearly impossible.

Additionally, government regulation of certain manufacturing processesmay require implementation of strict documentation and controlprocedures. For example, the Food and Drug Administration's (FDA's) 21Code of Federal Regulations Part 11 applies to records in electronicform that are created, modified, maintained, archived, retrieved, ortransmitted under any records requirement set forth in Agencyregulations, and to electronic records submitted to the Agency under theFederal Food, Drug, and Cosmetic Act an the Public Health Service Act.Part 11 includes provisions related to limiting system access toauthorized individuals, use of operational checks, use of authoritychecks, and use of electronic signatures. As biological control systemsmove towards electronic implementations, it is advantageous to designsystems to easily incorporate regulations governing electronic recordsand control procedures.

SUMMARY OF THE INVENTION

This invention relates to systems and methods for managing processconditions in a container or chamber, including controlling bioreactorsfor cell cultures and microbial fermentation, controlling semiconductorfabrication and controlling liquid chromatography. According to oneembodiment, the invention comprises a system for controlling a pluralityof different bioreactor processes in a plurality of bioreactors,comprising a first communication network, a second communicationnetwork, a first bioreactor configured to send a first data signalrelated to a condition in said first bioreactor, a second bioreactorconfigured to send a second data signal related to a condition in saidsecond bioreactor, a utility tower, coupled to said first and secondbioreactors, configured to receive the first and second data signals andsend first information based on the first data signal and secondinformation based on the second data signal over said first network, andconfigured to receive a first control signal for said first bioreactorand a second control signal for said second bioreactor over said secondnetwork and change a condition in said first bioreactor based on thefirst control signal and change a condition in said second bioreactorbased on the second control signal, and a controller, connected to saidutility tower by said first and second network, configured to receivethe information from said utility tower over said first network,determine the first control signal based on a first bioreactor processand/or the first information, and determine the second control signalbased on the second bioreactor process and/or the second information,and send the first and second control signals to said utility tower oversaid second network.

According to another embodiment, the invention comprises a system forcontrolling a bioreactor process, comprising a communication system, acontroller configured to receive information related to a condition in abioreactor, to control the bioreactor process by determining controlsignals based on the bioreactor process, and to send the control signalsover said communication system, and a utility tower, coupled to saidcontroller via said communication system, configured to receive thecontrol signals and to change a condition in the bioreactor based on thecontrol signals, said utility tower comprising a monitoring system thattransmits information related to a condition of the bioreactor to saidcontroller via said communication system, a bioreactor supply systemwhich supplies a substance to the bioreactor in response to a controlsignal, and an agitation system which agitates the solution in thebioreactor in response to a control signal.

According to yet another embodiment, the invention comprises a method ofcontrolling a benchtop bioreactor with a controller configured with asequence of steps and parameters of a bioreactor process and coupled toa bioreactor utility tower via a communication system, comprisingdetermining a control action to change a condition in the bioreactorbased on the sequence of steps of the bioreactor process, sending afirst signal from the controller to the bioreactor utility tower overthe communication system to direct the bioreactor utility tower toperform a first control action, and performing the first control actionto change the condition in the bioreactor.

According to yet another embodiment, the invention comprises a systemfor controlling a bioreactor process, comprising means for determining acontrol action to change a condition in the bioreactor based on thesequence of steps of the bioreactor process, means for sending a firstsignal from the controller to the bioreactor utility tower over thecommunication system to direct the bioreactor utility tower to perform afirst control action, and means for performing the first control actionto change the condition in the bioreactor.

In another embodiment, the invention comprises a system for monitoringand controlling a process in a controlled chamber, the processcomprising a sequence of steps and at least one parameter relating to acondition of the process, comprising a communication system, acontroller configured to receive information related to a condition inthe chamber, to control the chamber process by determining a controlaction required to carry out the process based on the chamber processsteps and the received information, to generate a control signalcorresponding to the control action, and to send the control signal oversaid communication system, and a utility tower, coupled to saidcontroller via said communication system, configured to provideinformation related to a condition in the chamber to said controller viasaid communication system, to receive the control signal from saidcontroller and to change a condition of the chamber based on the controlsignal, said utility tower comprising a monitoring system that transmitsinformation related to a condition of the chamber to said controller viasaid communication system, and a chamber supply system which supplies asubstance to the bioreactor in response to the control signal.

In yet another embodiment, the invention comprises a program storagedevice readable by a machine, tangibly embodying a program ofinstructions executable by the machine to perform a method ofcontrolling a benchtop bioreactor with a controller configured with asequence of steps and parameters of a bioreactor process and coupled toa bioreactor utility tower via a communication system, the methodcomprising receiving a measurement signal indicating a condition in thebenchtop bioreactor at the bioreactor utility tower, transmittinginformation related to the condition from the utility tower to thecontroller over the communication system, comparing the information to aparameter of the bioreactor process to determine a control action,sending a signal from the controller to the bioreactor utility tower viathe communication system to control the bioreactor utility tower toperform the control action, and performing the control action to changethe condition in the bioreactor.

BRIEF DESCRIPTION OF THE DRAWINGS

The above-mentioned and other features and advantages of the inventionwill become more fully apparent from the following detailed description,the appended claims, and in connection with the accompanying drawings inwhich:

FIG. 1 is a block diagram of a control system.

FIG. 2 is a more detailed block diagram of the utility tower part in thecontrol system.

FIG. 3 is a block diagram of a gas control system.

FIG. 4 is a block diagram of a pump control system.

FIG. 5 is a functional block diagram of the controller.

FIG. 6 is a functional block diagram of the computer contained in theutility tower.

FIG. 7 is a block diagram showing control systems networked together.

DETAILED DESCRIPTION

Embodiments of the invention will now be described with reference to theaccompanying Figures, wherein like numerals refer to like elementsthroughout. The terminology used in the description presented herein isnot intended to be interpreted in any limited or restrictive manner,simply because it is being utilized in conjunction with a detaileddescription of certain specific embodiments of the invention.Furthermore, embodiments of the invention may include several novelfeatures, no single one of which is solely responsible for its desirableattributes or which is essential to practicing the inventions hereindescribed. The scope of the invention should therefore be construed inaccordance with the appended claims and any equivalents thereof.

FIG. 1 is a high-level block diagram of a control system 100. Thecontrol system described herein has numerous control applications,including controlling chambers, or processing areas where it is usefulto have precise monitoring and application of gasses, fluids and solids.Examples of these application areas include, for example, highperformance liquid chromatography, semiconductor fabrication, foods,beverages, petroleum, chemicals, cell cultures and microbialfermentation.

In this embodiment, the control system 100 is shown to inter-operatewith two bioreactors 105, 110 which are controlled by a utility tower115 and a controller 120. Although shown as separate units in thisexample, the controller 120 and the utility tower 115 can also becontained in the same unit. The bioreactors 105, 110 can be any of anumber of types of bioreactors implementing a controlled process thatbenefits from monitoring conditions of the process and controllingfactors affecting the process, for example, microbial fermentation andcell cultures.

The bioreactors 105, 110 typically include a suitable container orvessel, and a headplate, which has connections 170, 175 to the utilitytower 115. Although the connections 170, 175 are depicted only by asingle line, the connections 170, 175 may include numerous wires, tubesor other means for communicating information or for transferringmaterial, for example, fluids, solids, or gases, between the utilitytower 115 and the bioreactors 105, 110. The bioreactors 105, 110 can bemonitored by sensors that measure the conditions (e.g., temperature, pH,dissolved oxygen, and level/foam) in the bioreactor at specified timesor continuously, and use the connections 170, 175 to the utility towerfor communicating sensor information. The connections 170, 175 caninclude gas lines that provide gas from the utility tower 115 to thehead space of the vessel and/or to sparge, i.e., near the bottom of thevessel so that the gas is emitted into a solution contained in thevessel. Such gasses can include, for example, nitrogen, oxygen, air, andcarbon dioxide, or another gas as required for a particular application.

The connections 170, 175 can also include tubes that carry fluids fromthe utility tower 115 to the bioreactors 105, 110. Fluids, for example,reagents, can be provided directly into the vessel to chemically changethe solution, or, fluids can be used to indirectly affect the process,for example the fluids can be used with a heating/cooling jacket. Theutility tower 115 can also use the connections 170, 175 to communicatecontrol signals to other devices that may be used to affect thebioreactors 105, 110, for example, an agitation motor, and opticaldensity, carbon dioxide, and glucose measurement devices.

The utility tower 115 includes devices, e.g., transmitters, that receivesensor data from sensors within the bioreactors 105, 110 and transmitinformation relating to the sensor data to a controller 120. The utilitytower 115 is also configured with devices to receive information fromcontrollable devices or equipment in, or attached to, the utility tower115 and transmit the information to a controller 120. The utility tower115 can include a human-machine interface (“HMI”) 125 that providesinformation to an operator of the control system. The HMI 125 can beconfigured to display information related to particular part of thecontrol system 100, or information related to several areas of thecontrol system or information relating to the entire control system. TheHMI 125 can be a display screen or a touch-screen display that can beused to interactively enter commands for the control system. In anotherembodiment, the utility tower 115 does not include a HMI 125. Instead,visual information is provided to the operator on a display screen atthe controller 120, or at a remote device, e.g., wireless device 155 oranother computer (not shown) in communication with the utility tower115.

The utility tower 115 can include an interface 150 that provides asuitable connection for various devices, e.g., a keyboard 130, and otherperipheral devices (not shown), e.g., a mouse, a printer, a local areanetwork (“LAN”), and/or a modem. In one example, the interface 150includes a USB port. In one embodiment, the utility tower 115 includesan interface (not shown) that allows communication with a wirelesscomputing device 155, e.g., a wireless tablet PC. Using the wirelesscomputing device 155, a user can remotely monitor the control system byreceiving information via a wireless connection 160 from the utilitytower 115 and/or change the control functionality by sending commandsvia the wireless link 160 to the utility tower 115.

A user can input information into the process control system 100 using adevice such as a mouse and/or a keyboard, or by using the touch-screenHMI 125, if the utility tower 115 is so configured. The utility tower115 can be configured without a display screen, for example, when aplurality of utility towers are connected on a network, discussedfurther below. In a network configuration, at least one of the utilitytowers will typically have a display screen to allow the user to receivethe system information, or there will be another display device in thecontrol system that conveys information relating to the control system100 to a user.

The network connections 135, 140, 145, which may also be referred toherein as busses or networks, provide three communication channels, inthis example, between the utility tower 115 and the controller 120. Inother example configurations, there can be more or fewer networkconnections between the utility tower and the controller 120. In oneexample configuration, communications described herein as using networkconnection 135 and the network connection 140 can use the same networkconnection between the utility tower 115 and the controller 120,assuming, of course, the utility tower 115 is configured with suitabledevices that can communicate via the same network bus. In anotherexample configuration, the utility tower 115 can use one bidirectionalbus to communicate with the controller 120. Network connections betweenthe utility tower 115 and the controller 120 may also be referred toindividually herein as a communication network and collectively as acommunication system. Using multiple types of network connections canallow a more cost-effective way to communicate information to thecontroller 120. For example, the complexity of the communication networkused for each monitoring and control device in a particular controlsystem configuration can be selected based upon the devices' particularcommunication requirements, thus minimizing expensive complex networkconnections when less expensive options are available.

The controller 120 controls and manages the utility tower 115functionality to implement a programmed process for the bioreactors 105,110. The controller 120 includes interface hardware and logic (e.g.,hardware, software and/or firmware) for each type of network busconnection 135, 140, 145. The controller 120 also contains hardware andlogic that receives information from the utility tower 115 and uses theinformation to monitor the bioreactors 105, 110 and control devices thataffect the conditions in the bioreactors 105, 110 in accordance withinstructions previously entered by a user, for example, in the form of acomputer program, or commands that are entered interactively by theuser. The controller 120 can also contain additional control andmanagement functionality, for example, for logging a history of theprocess conditions, conducting trend analysis, running diagnostics,performing maintenance of the control system, documenting specifiedevents, collecting audit trails on devices, requiring userauthorization, and performing change management.

A user typically interacts with the controller 120 through a deviceconnected to the utility tower 115, as described above. However, inanother embodiment the controller 120 can be connected to anotherdevice, for example, a stand-alone personal computer (“PC”), that allowsthe user to interact with the controller 120 by receiving informationfrom the PC's display screen and inputting information through the PC'skeyboard or mouse. To increase the reliability of the control system100, the controller 120 typically includes one or more sets of redundanthardware components that operate with one component “active” and theother component in “standby.” When the controller 120 includes redundantcomponents, it can be configured so that if an active component fails,its corresponding standby component automatically becomes active andruns the functionality that was being run by the failed component. Oneexample of a suitable controller 120 is the DeltaV™ MD Controller fromEmerson Process Management.

Exemplary ways of using and constructing embodiments of the controlsystem 100 are described in detail below with reference to FIGS. 2-7,which depict specific embodiments of the control system. Of course,because there are multiple ways to implement the control system, thefollowing description should not be taken to limit the full scope of theinvention.

Illustrative Embodiment

FIG. 2 is a more detailed block diagram of an example of the controlsystem of FIG. 1. The control system is configured to control twobioreactors, in this example. The control system shown in FIG. 2controls the processes occurring in two bioreactors 220, 220′ that areused for cell cultures. The bioreactors 220, 220′ are sometimes referredto herein as benchtop bioreactors as they are generally sized to fit ona bench or laboratory table. Of course, the bioreactors 220, 220′ can beplaced in any convenient location, e.g., the floor, and be sizedaccording to the process requirements. While this illustrativeembodiment relates to a control system that runs, monitors, and controlsa cell culture process, the control system can also be used for avariety of other processes that require monitoring process conditionsand providing gasses, fluids, solids, and agitation as required.

The bioreactors 220, 220′ can be glass or steel vessels and can be ofvarious sizes to contain, for example, a fraction of a liter of solutionor twenty liters or more of solution. The top or headplates and thevarious orifices and fittings of the bioreactors 220, 220′ are typicallymetal and can be manufactured from 316L stainless steel. The bioreactors220, 220′ are configurable in a variety of ways depending on therequirements of the application. For example, for growing cell culturesand microbial fermentation, the bioreactors 220, 220′ can be configuredwith sensors for measuring conditions of the contained solutions, anagitation device, and orifices or fittings connected to lines for addingfluids, for the intake and exhaustion of gases or for extractingsamples. According to an embodiment for processing cell cultures, abioreactor can include the following components: glass or steel vessel,headplate, motor coupler, marine impeller, pH housing, dissolved oxygen(DO) housing, thermowell, sparger pipe, air overlay pipe, triple port,septum holder, sample pipe, and a stand. According to an embodiment formicrobial fermentation, the bioreactor can include the followingcomponents: glass or steel vessel, headplate, motor coupler, rushtonimpeller, pH housing, thermowell, heat exchanger, baffles, triple port,septum holder, sample pipe and a stand. In either aforementionedembodiment, the bioreactor can also include the following components:motor, level/foam sensor and cable, water jacketed vessel, pH electrodeand cable, DO sensor and cable, temperature sensor and cable, heatingblanket, and an air outlet condenser. Bioreactors and the componentsdescribed herein are commercially available from Broadley-James ofIrvine, Calif.

As shown in FIG. 2, the control system includes a utility tower 115 anda controller 120 that manages (e.g., monitors, controls, and documents)conditions in two bioreactors 220, 220′. The controller 120 includesfunctionality that determines what control actions are required, e.g.,what services the utility tower 115 should provide to the bioreactors220, 220′, described in more detail hereinbelow. The controller 120 candetermine control signals corresponding to the control actions thatcontrol the utility tower 115 to provide, for example, a fluid, gas oragitation to the bioreactors 220, 220′, based on a programmed bioreactorprocess and/or based on information the controller 120 receives from theutility tower 115. When a controller 120 manages more than onebioreactor, it can determine control actions and a corresponding set ofcontrol signals for each bioreactor it manages. Functionality limitingaccess to the control system to authorized persons and requiringelectronic signatures, for example, user names and passwords, forcertain actions can also be included on the controller 120.

The utility tower 115 includes a bioreactor monitoring system that canmonitor the bioreactors 220, 220′ and send information related to thebioreactors 220, 220′ to the controller 120. In this example, themonitoring system includes dissolved oxygen transmitters 205, 205′, pHtransmitters 210, 210′, and temperature transmitters 215, 215′ thatmonitor conditions in the two bioreactors 220, 220′, respectively. Theutility tower 115 also includes a substance supply system which cansupply a gas, fluid or solid to the bioreactor. In this example, theutility tower 115 includes a gas control system 235 and a pump controlsystem 240 which are configured with a separate set of equipment tosupport each bioreactor 220, 220′, described further below. The utilitytower 115 also includes an agitation system which can agitate thebioreactors. In addition to simply agitating the solution in thebioreactors 220, 220′, the agitation system can change the partialpressure of the dissolved oxygen in the media by the level of agitationapplied. For example, increasing the level of agitation breaks thelarger bubbles of air or oxygen enriched air, that is being provided tothe bottom of the bioreactor, into smaller bubbles. It follows that thisincreases the total surface area of the oxygen bubbles and allows moreoxygen into the media. In this example, the agitation system includesattached agitation units 260, 260′. Typically, the configuration of themonitoring system, the substance supply system, and the agitation systemare similar for each bioreactor, however, they can be configured so eachbioreactor 220, 220′ is supported with different transmitters, differentagitation units and different configurations for systems supplying gas,fluid, or solids in order to support two different applications. Inother embodiments, a utility tower can be configured to support morethan two bioreactors. Although sometimes referred to herein in thesingular for ease of reference, the devices, systems, and modulesdescribed herein are applicable for monitoring and controlling bothbioreactors 220, 220′.

As illustrated in the embodiment shown in FIG. 2, the utility tower 115and the controller 120 communicate using multiple busses 135, 140, 145.Although shown as wired busses in FIG. 2, one or more of the busses 135,140, 145 can be implemented using wireless links. In this embodiment,the utility tower 115 communicates information from the DO transmitters205, 205′, the pH transmitters 210, 210′, and the temperaturetransmitters 215, 215′ to the controller 120 through a H1 FOUNDATION™fieldbus 135. FOUNDATION™ fieldbus is an all-digital, serial, two-waycommunication network that can communicate multiple variables from onefield device over the same pair of wires. The H1 implementation ofFOUNDATION™fieldbus works at 31.25 Kbit/sec and can connect to multiplefield devices providing communication and power over standard twistedpair wiring. FOUNDATION™ fieldbus technology is known in the art andcommercially available from Emerson Process Management in Austin, Tex.

In this example, the computer 225 communicates with the controller 120over an Ethernet bus 140, a well known and relatively inexpensivedigital network. For example, Ethernet is used by the computer 225 tocommunicate commands and instructions received from an operator using alocal input device 280, for example, a keyboard, a mouse, or a wirelesscomputing device, to the controller 120. The controller 120 includes aEthernet switch/hub 265 that allows the computers of multiple utilitytowers to be connected and controlled by a single controller 120.

The gas control system 235, the pump control system 240 and theagitation units 260, 260′ communicate with the controller 120 through aDeviceNet Gateway 230 and a DeviceNet bus 145, according to thisembodiment. DeviceNet is a low-cost communications link typically usedfor connecting industrial devices (such as limit switches, photoelectricsensors, valve manifolds, motor starters, process sensors, bar codereaders, variable frequency drives, panel displays and operatorinterfaces) to a network to eliminate expensive hardwiring. The directconnectivity of the DeviceNet bus can provide improved communicationbetween devices as well as important device-level diagnostics not easilyaccessible or available through hardwired I/O interfaces. DeviceNetgateways and networks are well known in the art and are available fromInterlink BT in Pennsylvania. In another embodiment, the gas controlsystem 235, the pump control system 240 and the agitation units 260,260′ communicate with the controller 120 using a Profibus DP Gateway anda Profibus bus instead of the DeviceNet Gateway 230 and DeviceNet bus145. Profibus buses are known in the art and are available fromInterlink BT in Pennsylvania.

The control system can include functionality for measuring the dissolvedoxygen in each bioreactor 220, 220′. In this example, the utility tower115 includes two dissolved oxygen (“DO”) transmitters 205, 205′configured such that each DO transmitters 205, 205′ receives informationfrom a DO sensor in one of the bioreactors 220, 220′. Although eitherthe percentage of dissolved oxygen or the partial pressure of dissolvedoxygen can be calculated by the DO transmitters 205, 205′, in thisexample the partial pressure of dissolved oxygen is calculated. Duringcalibration of the DO sensor, the DO transmitter 205 calculates andsaves dissolved oxygen span and slope measurements that set the offsetof the sensor to zero and calculate the value for a 100% signal from thesensor. The DO sensor is configured to contact the solution in thebioreactor 220 and communicate analog signals to the DO transmitter 205related to the dissolved oxygen in the solution and the temperature ofthe solution. The DO transmitter 205 converts the analog signals todigital signals and calculates the partial pressure of dissolved oxygenof the solution. The DO transmitter communicates a value related to theactual output signal of the DO sensor, temperature information, a valuerelated to the partial pressure of oxygen, and the slope and spancalibration values as multiple channel digital data to the controller120 over the FOUNDATION™ fieldbus 135. A dissolved oxygen sensor anddissolved oxygen transmitter as described above are commerciallyavailable from Broadley-James of Irvine, Calif. and Emerson ProcessManagement of Irvine Calif., respectively.

The control system can also measure the temperature of the solution ineach bioreactor 220, 220′ and communicate temperature information to thecontroller 120. The utility tower 115 includes two temperaturetransmitters 215, 215′, which receive information from remotetemperature devices (“RTD”) in the bioreactors 220, 220′, respectively.The RTD includes a single temperature sensors that provide an analogsignal to the temperature transmitter 215 indicating a temperaturemeasurement of the solution in the bioreactor 220. In anotherembodiment, the RTD includes two temperature sensors and provides twotemperature measurements. The temperature transmitter 215 converts thereceived analog signals to digital signals, and calculates the “drift”of the first temperature measurement using the second temperaturemeasurement. The temperature transmitter 215 communicates temperatureinformation, including the first and second temperature measurements,the status of the RTD (i.e., whether it is in or out of range), and thecalculated temperature “drift,” to the controller 120 over theFOUNDATION™ fieldbus 135. A RTD as described herein is commerciallyavailable from Burns Engineering of Wisconsin. A temperature transmitteras described herein is available from Emerson Process Management ofMinnesota.

The control system also includes functionality that measures the pH ofthe solution in each bioreactor 220, 220′. The pH transmitters 210, 210′communicate pH information from pH sensors located in the bioreactors220, 220′ to the controller 120. A pH sensor in each of the bioreactors220, 220′ sends an analog signal that is related to a pH measurement of0-14 to its corresponding pH transmitter 210, 210′. The pH transmitter210 can analyze the raw pH signal received from the pH sensor and otherdata, including values for span and offset obtained from calibration ofthe pH sensor, the reference impedance, and the glass impedance, todetermine if they are within specified range. The pH transmitter 210converts the analog signal from the pH sensor to a digital signal, andcommunicates values related to span, offset, the raw signal from the pHsensor, pH value, reference impedance, and glass impedance to thecontroller 120 through the FOUNDATION™ fieldbus 135. A pH sensor asdescribed herein available from Broadley-James of Irvine, Calif. A pHtransmitter 210 as described herein are commercially available fromEmerson Process Management of Irvine, Calif. respectively.

Agitation units 260, 260′ are included in the control system and provideagitation to the solutions contained in the bioreactors 220, 220′. Inthis example, the agitation unit 260 includes an impeller that isimmersed in the solution, a motor that drives the impeller and a digitalmotor controller. The agitation motor signal comes off the motor via adigital encoder and goes to the motor controller. The digital motorcontroller signal (e.g., RPMs of the motor) goes to the DeviceNetgateway 230 which then sends the data through the DeviceNet bus 145 tothe controller 120. As such, the controller 120 is then able to controland adjust the agitation unit 260 based on the needs of the process orchanges by the operator. The agitation units 260, 260′ are availablefrom Maxon Motors, Switzerland.

As shown in FIG. 2, the control system includes an embedded personalcomputer (“PC”) 225 in the utility tower 115. The computer 225 can be auni-processor or multi-processor machine, and include an addressablestorage medium or computer accessible medium, for example, random accessmemory (RAM), and a hard disk and/or removable media, e.g., floppydisks, laser disk players, digital video devices, compact disks, ormagnetic optical tapes. The computer 225 can execute an appropriateoperating system such as Linux, Unix, any of the versions of MicrosoftWindows, Apple MacOS, IBM OS/2 or any other operating system that canoperate compatibly with the software running on the controller 120. Thecomputer 225 includes logic that runs the HMI, displaying, for example,system information received from the controller 120 or informationreceived from an input device. If the HMI is a touchscreen, the computer225 includes logic which manages its input/output functionality. Thecomputer 225 also includes logic which communicates an operator'scommands received from an input device or a touchscreen to thecontroller 120 over the Ethernet bus 140. The computer 25 can alsoinclude, among other things, functionality for tracking andelectronically logging historical system data, obviating the need forpaper-based operator logs. Although the computer 225 is shown in thisexample to be contained in the utility tower 115, in other embodimentsit could be located with the controller or as a separate unit incommunication with the controller. The computer 225 is described furtherin connection with FIG. 6.

A gas control system 235 contained in the utility tower 115 provides thebioreactors 220, 220′ with gasses, for example, air, oxygen, nitrogen,and carbon dioxide, as required for a particular application. The gascontrol system 235 can provide a single gas or a mixture of two or moregasses. Sources for the gasses are connected to input fittings in theutility tower 115. Gas control instructions which are included in theprocess control program running on the controller 120 and/orinstructions interactively entered by an operator, control the gascontrol system 235 to provide a desired type of gas in a measuredquantity to the bioreactors 220, 220′. The gas control system 235provides the desired gas to either the “head space” of the bioreactors220, 220′ or to “sparge,” i.e., so gas entering the bioreactors 220,220′ flows into the solution contained therein. The controller 120communicates with the gas control unit 235 through the DeviceNet bus 145and the DeviceNet Gateway 230, described further hereinbelow.

A pump control system 240 contained in the utility tower 115 providesthe bioreactors 220, 220′ with various types of fluids. Pump controlinstructions, included in the process control program running on thecontroller 120 and/or instructions that are interactively entered by anoperator, control the pump control system 240 to provide a desired typeof fluid in a measured quantity to the bioreactors 220, 220′. The pumpcontrol system 240 can be connected to a media vessel provided by theoperator and used to pump the provided media into a bioreactor 220.Alternatively, the pump control system 240 can used to remove solutionor media from the bioreactor 220 for testing or processing. Thecontroller 120 communicates with the pump control system 235 through theDeviceNet bus 145 and the DeviceNet Gateway 230, described furtherhereinbelow. The pump control system 240 described for this embodimentand shown in FIG. 2 and FIG. 4 includes two pump heads, two pump motorsand two pulse amplification circuits for each bioreactor 220, 220′. Inother embodiments, the pump control module 240 can include one pump ormore than two pumps for each bioreactor 220, 220′.

The control system can be configured to support many differentapplications, for example, controlling a process in a chamber or anotherenclosed or controlled environment, and which may require the devicesand systems described herein, and/or other suitable monitoring devicesand systems which are controllable to affect the particular application.To support other applications, the utility tower 115 can be configuredwith suitable transmitters that allow other sensors and analyzers to becoupled to the utility tower 115, instead of, or in addition to, theabove-described sensors, including, e.g., for carbon dioxide, pressure,or conductivity. The utility tower 115 receives signals from the othersensors and analyzers coupled to the utility tower 115 and sendsinformation related to the signals to the controller 120 over the firstcommunication network 135.

In another embodiment, the control system can survey, electronicallyrecord and display information from other devices. For example, thecontrol system can receive data from and control one or more stand-alonedevices 255, 255′. Examples of a stand-alone device 255 include a devicefor measuring glucose, carbon dioxide, cell count, and cell viability ofthe solution in the bioreactors 220, 220′, banks of peristaltic pumpsthat are outside of the utility tower, or a weigh scale. A stand-alonedevice 255 may include a connection 270 to the bioreactor 220 thatallows the device to retrieve a sample, or a connection 270 to a sensorin the bioreactor 220. Alternatively, a stand-alone device 255 mayrequire the sample to be placed in the device.

The manner of coupling a stand-alone device 255 to the control systemdepends on its particular configuration. The stand-alone device 255 canbe coupled directly to the communication system for direct communicationwith the controller 120 if its output is compatible with, for example,FOUNDATION™ fieldbus 135. For example, a device 255 that monitors cellcount and cell viability can provide data, for example, the number ofcells per a designated quantity, cell size, percentage of cellviability, total number of cells, and an image of the cells in thesample, directly to the controller 120 via the Foundation™ fieldbus.Alternatively, the output of the stand-alone device 255 can be coupledto a suitable transmitter in the utility tower 115, and the utilitytower 115 can be configured to send information relating to the datafrom the stand-alone device 255 to the controller 120 via theFOUNDATION™ fieldbus 135. When the output of the stand-alone device 255is not directly compatible with a transmitter or the communicationsystem of the control system, for example, the output signal from aglucose analyzer through a RS232 connection, a converter may first berequired to change the output signal from the stand-alone device 225 toa compatible signal.

In another example embodiment, the utility tower 115 can also beconfigured with devices 250, 250′ which can be, for example, temperaturecontrol systems. The devices 250, 250′ are coupled to discrete I/Oblocks in the utility tower 115, and the discrete I/O blocks are coupledto the DeviceNet Gateway 230. The utility controller 120 communicatesinformation for controlling these devices 250, 250′ with the utilitytower 115 via the DeviceNet bus 145. For example, to control atemperature control system, the controller 120 can receive temperatureinformation related to the media in a bioreactor 220 from the utilitytower 115 via the FOUNDATION™ fieldbus 135, determine if the mediatemperature should be increased or decreased, generate the correspondingcontrol signal to increase or decrease the temperature of the media, andcommunicate the control signal to the utility tower 115 via theDeviceNet bus 145. In response to the control signal the utility tower115 receives from the controller 120, the utility tower 115 communicatesa signal, via the DeviceNet Gateway 230 and the discrete I/O block, tothe temperature control system to increase or decrease the temperatureof the media.

One example of a temperature control system is a “cold finger” which isgenerally used to remove heat from the media. In this example, the coldfinger is connected to a water source and a water drain line, and it isplaced into the bioreactor so that the cold finger contacts the media. Acontrollable valve (not shown), which is positioned between the watersource and the cold finger and can be modulated to control the flow ofwater through the cold finger, can be connected to an discrete I/O blockin the utility tower 115. The discrete I/O block is coupled to theDeviceNet Gateway 230. The controller 120 sends control signals to thecontrollable valve to open or shut the valve, thus increasing ordecreasing the flow of water through the cold finger and correspondinglyincreasing or decreasing the amount of cooling provided by the coldfinger.

Another example of a temperature control system is a double-walledvessel system where water is circulated between the walls to provideboth heating and/or cooling of the media to maintain a desiredtemperature. The double-walled vessel system can be coupled to anappropriate controller, which is coupled to the DeviceNet Gateway 230,and the controller provides the double-walled vessel system with avariable signal (e.g., 0-5 volts) that controls the temperature of theof the double-walled vessel system. The controller 120 receivestemperature information related to the media and sends temperaturecontrol signals to the utility tower 115, as described above, and theutility tower 115 provides the variable signal to the double-walledvessel system via the DeviceNet Gateway 230 and the controller coupledto the double-walled vessel system .

In another example of a temperature control system is a “heatingblanket” which wraps around the bioreactor. In this example, the heatingpad is coupled to the utility tower 115, which provides power to theheating blanket and controls the on/off state of the heating blanket.Typically, the heating blanket is coupled to a discrete I/O block whichis coupled to the DeviceNet Gateway 230. The controller 120 receivestemperature information related to the media and sends temperaturecontrol signals to the utility tower 115, as described above. Inresponse to the control signals, the utility tower 115 controls the heatprovided to the media from the heating blanket, via the DeviceNetGateway 230 and the discrete I/O block coupled to the heating blanket,by switching the heating blanket on and off.

In yet another example embodiment, a control system for high performanceliquid chromatography (“HPLC”) includes sensors coupled to correspondingtransmitters in the utility tower 115 for monitoring pH, temperature,conductivity, and pressure of a HPLC separator (e.g., at its inlet andoutlet). The utility tower 115 sends information related to thesecharacteristics to the controller 120 via FOUNDATION™ fieldbus 135. Itis contemplated that a HPLC control system can be configured to control,among other things, the pressure in a HPLC separator in various ways,including, for example, by regulating the pressure of fluid flowing intothe separator, or through the use of a piston in the separating tube toforce the fluid through the separating medium, or by moving a diaphragmin the separator tube to increase or decrease the pressure. To controlthe pressure in the separator, suitable control devices for controllingthe fluid pressure, the piston, or the position of the diaphragm can beconnected to the DeviceNet Gateway 230. The controller 120 can beconfigured to determine control signals to increase or decrease thepressure in accordance with a programmed process and/or monitoredconditions of the separator (e.g., pressure) and send the controlsignals to the utility tower 115 via the DeviceNet bus 145. The HPLCcontrol system can also include a fluid controller, functionally similarto the above-described gas MFC, to precisely regulate the amount offluid flowing into the separator.

In another embodiment, a control system can be configured to supportapplications for the petroleum industry. For example, a control systemcan control a supply system, such as a peristaltic pump, to preciselyadminister additives for a petroleum product, such as the quantity ofred dye added to gasoline, or other desired additives.

In the semi-conductor field, a control system can be configured toactively control gasses used for wafer production by monitoring theamount of gas in a process chamber with suitable sensors, and providinggasses to the process chamber based on the monitored gas levels and adefined process programmed into the control system. A control systemsupporting semiconductor fabrication can also include other specializedmonitoring equipment, for example, temperature sensors that sendtemperature data of the chamber and/or of the surface of the wafer tothe utility tower 115, which passes information related to thetemperature data to a controller 120 via the FOUNDATION™ fieldbus 135 asin input for the control process. A control system may also includeheating and cooling devices (e.g., a quartz heater) that are coupled tothe utility tower 115 via the DeviceNet Gateway 230, and controlled bysignals sent from the controller 120 to the utility tower 115 via theDeviceNet bus 145 in accordance with the process steps and parametersprogrammed in the controller 120.

Additionally, the foregoing control system can be configured to helpmanage a supply and inventory process. In one example, the controlsystem includes an input device, for example, a bar code scanner,coupled to the utility tower by a USB port at the interface connection150 (FIG. 1). Suitably coded consumables that are used in the processsupported by the utility tower are identified by the bar code scanner,and the control system records and tracks which consumables have beenused. In one example, the control system can send the informationrelating to the use of the consumable to another system, e.g., aninventory or supply system, via the Ethernet bus 140 or another suitablecommunication network, which can use the information to help manage thesupply of consumables for the lab.

In another example configuration, the utility tower 115 can be coupledto a weigh scale 255, and the controller 120 is configured to usefeedback from the weigh scale 255 to control the amount of fluidprovided by the pump control system 240 or another substance deliverysystem. The weigh scale 255 can be positioned to weigh the bioreactor220 or a substance, for example, a reagent, provided to the bioreactor220. Alternatively, the weigh scale 255 can be configured to providedata via an output connection, for example, Profibus, that allows it tocommunicate directly with the controller 120 via a Profibus connection135. In another example, the scale provides a stream of pulses where therate of the pulses changes based on the weight measurement. In thislatter example, the weigh scale is coupled and provides pulses to an I/Oconnection in the utility tower 115, which communicates the pulseinformation to the controller 120 via the DeviceNet bus 145. Based onthe feedback from the weigh scale 255, the controller 120 can send acontrol signal to the utility tower 115 to provide or remove a desiredamount of fluid or media using the pump control system 240.

The control system can keep the solution in the bioreactor at a desiredlevel that can be programmed into the controller 120 by using the pumpcontrol system 240. In one example configuration, the weigh scale 225weighs the bioreactor 220, as described above, and the pump controlsystem 240 receives control signals from the controller 120 to provideor remove fluid to maintain a desired level. In another exampleconfiguration, a level detector is coupled to a corresponding discreteI/O block in the utility tower 115 and provides information related tothe level of the solution in the bioreactor 220. The utility tower 115communicates solution level information to the controller 120 via theDeviceNet bus 145, and the controller 120 can send a control signal tothe utility tower 115 to provide or remove a desired amount of fluidusing the pump control system 240 to maintain the desired level. Inanother example configuration, the weigh scale 225 weighs the fluidremoved from the bioreactor 220 and this information is communicated tothe controller 120 by the utility tower 115 via the DeviceNet bus 145.The controller 120 can be programmed with the fluid's weight, determinethe amount of fluid required to compensate for the fluid removed, andsend a control signal to the utility tower 115 to provide the properamount of fluid using the pump control system 240.

In another embodiment, the control system can use a gravity flow systemto feed substances, including fluids, to the bioreactors. A second tower(not shown), referred to herein as an accessory tower, can be includedin the control system and configured to include a coriolis meter (notshown) which provides precise metering for a gravity fluid flow. Theaccessory tower can be coupled to the utility tower 115 via theDeviceNet Gateway 230. Alternatively, the accessory tower can beconnected to the controller 120 over a DeviceNet bus 145. In eitherconfiguration, the controller 120 receives fluid flow information fromthe accessory tower and sends signals to the accessory tower thatcontrol the flow of the fluid via the DeviceNet bus 145. The accessorytower, when suitably positioned relative to the bioreactor, thusprovides a controlled fluid flow to the bioreactor with out the use of apump. In another embodiment, the control system can include a pumpcontrol system 240 configured to provide a fluid to a bioreactor 220using compressed air to facilitate the flow of the substance to thebioreactor 220.

Turning now to FIG. 3, the gas control system 235 is shown in furtherdetail, according to one embodiment. The gas control system 235 containstwo sets of gas control devices, each set supporting one of thebioreactors 220, 220′. For example, one bioreactor 220 is supported by afirst set of thermal mass flow controllers 304, 306, 308, 310, 312,valves, for example, solenoid check valves 324, 326, 328, 330, 332, anddirectional three-way valves, such as three-way solenoid valves 344,346, 348. Similarly, a second bioreactor 220′ is supported by a secondset of mass flow controllers 314, 316, 318, 320, 322, solenoid checkvalves 334, 336, 338, 340, 342, and directional three-way solenoidvalves 350, 352, 354.

Supply lines for oxygen, nitrogen, carbon dioxide and air are connectedto input fittings (not shown) on the utility tower 115. As shown in FIG.3, oxygen, nitrogen and carbon dioxide can have a similar gas flow paththrough the gas control system 235. For example, oxygen flows throughthe solenoid check valve 326, through the thermal mass flow controller(“MFC”) 306, and then through the directional three-way solenoid valve344 which directs the oxygen to a connection with the head space h orsparge s of the bioreactor 220. The solenoid check valves 324, 326, 328,330, 332, 334, 336, 338, 340, 342 receive open and close control signalsfrom the controller 120 via from a relay discrete I/O (not shown), whichis connected to the DeviceNet Gateway 230 (FIG. 2).

According to one embodiment, the gas control system 235 includes fiveMFC's, one MFC each for oxygen 306, nitrogen 308, carbon dioxide 310,and two MFC's for air 304, 312. In other embodiments, the gas controlsystem 235 can be configured to have fewer or more MFC's, and differentgases may be desired and appropriately used instead of theaforementioned gases. Each MFC includes a measuring element thatmeasures the amount of gas passing through the MFC and an electricallyactuated solenoid valve that modulates to let the gas flow through theMFC based on a control signal the MFC receives from the controller 120via the DeviceNet Gateway 230. The MFC also includes a transmitter thatsends the position of the solenoid valve, the gas flow rate measurement,and the temperature of the gas to the controller 120 via the DeviceNetGateway 230. Typically, closing the solenoid valve in the MFCeffectively shuts off 99.7% of the gas flow through the MFC. Using aseparate solenoid check valve, such as solenoid check valve 326, ensuresthe gas flow is completely stopped and accordingly permits more accurateprocess control.

As illustrated in FIG. 3, the three-way solenoid valves 344, 346, 348direct the flow of oxygen, nitrogen, and carbon dioxide, respectively,to either the head space (indicated by “h”) or sparge (indicated by “s”)of a connected bioreactor 220. The gas control system 235 includes twoMFC's 305, 312 for air. Air flowing through one MFC 304 flows to thehead space of a bioreactor, while air flowing through the other MFC 312provides air to sparge the bioreactor. The three-way solenoid valves344, 346, 348, 350, 352, 354 receive signals to align the three wayvalve to either sparge or head space, or to close the valve from thecontroller 120 via a relay discrete I/O (not shown) which is connectedto the DeviceNet Gateway 230. In one example, the gas control system 235can provide two or more gasses to the bioreactor 220 by mixing thegasses in a common delivery tubing or manifold (not shown) before thegasses enter the bioreactor 220.

FIG. 4 illustrates the pump control system 240 configured to control twopumps for each of the bioreactors 220, 220′ (FIG. 2), according to oneembodiment. The pump control system 240 includes pump modules 405, 425,430, 435, with pump module 405 shown expanded to provide more detail.The description hereinbelow is for pump module 405 but it also appliesto the other pump modules 425, 430, 435 as they are typicallyconfigured. Pump module 405 includes a peristaltic pump 415 that isdriven by a brushless motor 410. The peristaltic pump 415 moves fluidthrough a length of flexible tubing to a bioreactor by using rotorsoutside the tubing to push the fluid through the tube. The motor 410and, correspondingly, the peristaltic pump 415, is controlled by varyingthe voltage applied to the motor 410, for example, between zero and fourvolts. In accordance to the process programmed into the controller 120,or in response to interactively entered pump control commands, thecontroller 120 causes the peristaltic pump 415 to provide fluid to thebioreactor by communicating a control signal to the DeviceNet Gateway230, which controls the amount of voltage applied to the motor 410. Thepump control system 240 can be used to provide fluid to or remove fluid(e.g., for harvesting, transferring, or sampling) from the bioreactor220.

The pump module 405 includes a pulse amplification circuit 420 withconnections 421, 422 to the wires supplying power to the motor 410. Thepulse amplification circuit 420 detects and amplifies high frequency“pulses” that are generated by the motor 410 and provides the pulses asfeedback to the controller 120. The number of pulses the motor generatesis directly related to the movement of the motor, and, accordingly, therotation of the pump. The controller 120 includes functionality thatdetermines the number of pump revolutions per minute (“RPM”) by countingthe number of pulses it receives from the pulse amplification circuit420. In this embodiment, for example, 32,000 pulses are equivalent toone revolution of the pump rotors. As the peristaltic pump 415 iscalibrated to provide a known amount of fluid per revolution, thecontroller 120 can use the pulses as a feedback mechanism and thus moreaccurately control the amount fluid provided by the pump 415. Forexample, the typical accuracy of a peristaltic pump is within about 4-5%of the desired amount. By controlling the pump using the pulseamplification circuit 420, the accuracy of the peristaltic pumpdramatically increases so that the provided amount of fluid is withinabout 0.5% of the desired amount. The calculated pump RPM can also besent from the controller 120 to the embedded PC which displays the RPMon the HMI. A peristaltic pump as described hereinabove is availablefrom Watson Marlow of Bredel, England.

FIG. 5 illustrates a block diagram of the controller 120. One example ofa suitable controller 120 is the DeltaV™ MD Controller from EmersonProcess Management. According to one embodiment, the controller 120includes DeltaV™ control system software 555 (“DeltaV”) from EmersonProcess Management. Alternatively, other suitable control systemsoftware incorporating the functionality described herein can also beused. The control system software 555 can include one or more subsystemsor modules. As can be appreciated by a skilled technologist, each of themodules can be implemented in hardware or software, and comprise varioussubroutines, procedures, definitional statements, and macros thatperform certain tasks. Therefore, the following description of each ofthe modules is used for convenience to describe the functionality of thecontrol system. In a software implementation, all the modules aretypically separately compiled and linked into a single executableprogram. The functionality described herein for each of the modules maybe arbitrarily redistributed to one of the other modules, combinedtogether in a single module, or made available in, for example, ashareable dynamic link library. These modules may be configured toreside on addressable storage medium and configured to execute on one ormore processors. Thus, a module may include, by way of example, othersubsystems, components, such as software components, object-orientedsoftware components, class components and task components, processes,functions, attributes, procedures, subroutines, segments of programcode, drivers, firmware, microcode, circuitry, data, databases, datastructures, tables, arrays, and variables.

To implement a particular bioreactor cell growth process, the controlsystem software 555 is configured with the characteristics of thehardware and software for the desired control system. Duringconfiguration, a graphical representation of the control system isdefined. The control system software includes images of equipment, e.g.,check valves, three-way valves, pumps, tubing, vessels, etc., that areused to build a displayable representation of the desired controlsystem. Characteristics of the control system equipment system that arerequired for control and communication are programmed into the controlsystem software 555 and associated with the appropriate image. Onceconfigured, the control system software 555 can display therepresentation of the control system or portions thereof, andinformation that relates to the control system, on the HMI or anothersuitable display device, while the control system is running the cellculture growth process. The information displayed can include, forexample, temperature, pH, DO, agitation speed, valve alignment,headspace gas data, sparge gas data, pump data including revolutions andquantity, gas flow data.

The steps, parameters and conditions of the desired cell culture processare entered into the control system software 555. The steps, parametersand conditions can include, for example, defining when, in relation totime or to a monitored condition, and in what amount, gas, fluid, and/oragitation is provided to a bioreactor. Once a cell culture process isproperly entered, the control system software can run the process inaccordance with the predefined steps and conditions, consistentlyreproducing the process and electronically logging events and conditionsoccurring during the process.

The controller 120 includes a FOUNDATION™ fieldbus interface 505connected to the FOUNDATION™ fieldbus 135, a DeviceNet interface 510connected to the DeviceNet bus 140, and a Ethernet interface 515connected to the Ethernet bus 145. The control system software 555 usesthe interfaces 505, 510, 515 to communicate with the utility tower 115,the devices contained therein and attached thereto. In this embodiment,the control system software 555 receives information from the pHtransmitters 210, 210′ the temperature transmitters 215, 215′, and theDO transmitters 205, 205′ using the FOUNDATION™ fieldbus interface 505.The control system software 555 communicates with the DeviceNet Gateway230 via the DeviceNet Interface 510, and communicates with the computer225 via the Ethernet bus 140.

The control system software 555 can include a diagnostic and maintenancemodule 560 that runs diagnostic checks on the control system and alertthe operator to maintenance actions that are required, includingpredictive maintenance actions. The control system software 555 can sendthe diagnostic and maintenance data to the computer 225, via theEthernet bus 140, where the data can be stored in memory.

The control system software 555 can also include a module 550 thatelectronically logs events occurring in the control system, therebyeliminating the need to keep paper-based operator logs. For example,information that the control system software 555 receives from theutility tower 115 relating to the temperature, pH or the partialpressure of dissolved oxygen of the solution in the bioreactors can beelectronically logged and date/time stamped. Events or control actionsstarted or stopped by the control system software 555 can also beelectronically logged and date/time stamped. For example, when thecontrol system software 555 sends a signal to the utility tower 115 toprovide gas, fluid or agitation to the bioreactors, the start and stoptimes for that events can be recorded by the event logging module 550.Information sent from the utility tower 115 to the control systemsoftware 555, relating to the amount of gas or fluid provided to thebioreactor, or the RPM's of an agitation unit, can also beelectronically logged by the control system software 555 to maintain anelectronic history of the process. The control system software 555 cansend the electronic logs, via the Ethernet interface 515, to thecomputer 225 which stores them in memory, for example, on its hard disk.In other embodiments, the electronic logs may be stored in othersuitable locations, e.g., on a PC or a dedicated storage medium incommunication with the controller 120.

In this illustrative embodiment, the controller 120 is configured withDeltaV control system software 555 which manages the cell cultureprocess by monitoring and controlling the conditions in the bioreactor.To monitor the process, DeltaV 555 receives information relating to theconditions of the solution in the bioreactors. In this example, duringthe cell culture growth process DeltaV 555 receives temperature, pH, anddissolved oxygen information from the temperature transmitters 215,215′, pH transmitters 210, 210′ and the DO transmitters 205, 205′ viathe FOUNDATION fieldbus interface 505. DeltaV 555 includes a temperaturemodule 520, a pH module 525 and a dissolved oxygen module 530 which canprocess the information from the transmitters to determine if thetemperature, pH and the DO of the solution are within parameters thatwere programmed while configuring DeltaV for the particular cell cultureprocess. The temperature module 520, a pH module 525 and a dissolvedoxygen module 530 can also provide the current temperature, pH, and DOfor display on the HMI. If the temperature, pH or DO of the solutionfalls outside of its parameters, DeltaV 555 can determine whether toexecute a control action, for example, providing gas, fluid or agitationto the solution, to bring the condition back within its parameters.

DeltaV 555 can include an agitation control module 535 that can send acontrol signal via the DeviceNet interface 510 to cause an agitationunit to agitate the media in the bioreactor 220. In many cell cultureand microbial fermentation processes, agitation is provided continuouslyor nearly continuously. The agitation control module 535 can also sendthe agitation control signal as part of the normal programmed cellculture process, i.e., if agitation is required at a specified time inthe process. Or, the agitation control module 535 can send an agitationcontrol signal based on a monitored condition relative to a specifiedset-point that is programmed into DeltaV, e.g., the level agitation canbe increased or decreased as the monitored condition becomes closer toor further from the specified set-point. Alternatively, the agitationcontrol module 535 can control an agitation unit to provide agitation tothe solution based on commands that are interactively entered by anoperator on the HMI or by another input device.

In this example, DeltaV 555 also contains a gas control module 545 thatsends control signals via the DeviceNet interface 510 to cause the gascontrol system 235 (FIG. 3) to provide gas to the bioreactor to, forexample, change a chemical characteristic of the solution in thebioreactor e.g., pH. In this embodiment, the gas control module 545 canprovide air, oxygen, nitrogen, carbon dioxide or a mixture of any of thegasses to the head space or sparge of the bioreactor. For example, toprovide oxygen to a bioreactor, the gas control module 545 can sendcontrol signals to the gas control system 235 (FIG. 3) that open theoxygen check valve 326, open the valve in the oxygen MFC 306, and openthe oxygen directional three-way solenoid valve 344, allowing gas toflow to either head space or sparge. The gas control module 545 candetermine the amount of oxygen being provided to the bioreactor byprocessing gas flow information it receives from the MFC via theDeviceNet Gateway 230. When the desired amount of oxygen has beenprovided, the gas control module 545 sends control signals via theDeviceNet Gateway 230 to close the oxygen solenoid check valve 326, thevalve in the oxygen MFC 306 and oxygen directional three-way valve 344.The gas control module 545 can also change the gas flow rate as a resultof information that the controller 120 receives, e.g., informationrelated to the partial pressure of oxygen or pH of the media. Forexample, to control the partial pressure of oxygen, the gas controlmodule 545 can increase the rate that the gas control system 235provides oxygen to the bioreactor 220 as the difference between themonitored partial pressure and the desired partial pressure increases,and correspondingly decrease the rate that the gas control system 235provides oxygen to the bioreactor 220 as the difference between themonitored partial pressure and the desired partial pressure decreases.

The control system software 555 contains a pump control module 540 thatcan send a control signal via the DeviceNet interface 510 to cause thepump control system 240 (FIG. 2) to provide a fluid to the bioreactorto, for example, change a chemical characteristic of the solution in thebioreactor, or change the temperature of the solution by providing fluidto circulate in a water-jacketed bioreactor vessel or by directlyintroducing a fluid into the solution. The pump control module 540 canincrease or decrease the rate at which a fluid is provided to abioreactor 220 in response to a measured condition, e.g., pH, in thebioreactor 220. Each revolution of the rotors of the peristaltic pump inthe control system causes a known and consistent amount of fluid to flowthrough the tube connected to the pump. The characteristics of aperistaltic pump, including its fluid flow per rotor revolution and thenumber of high frequency pulses associated with each rotor revolution,can be programmed into DeltaV 555 during the control systemconfiguration. When the peristaltic pump is activated, the pump controlmodule 545 receives, via the DeviceNet Gateway 230, high frequencypulses from the pulse amplification circuit 420 (FIG. 4), describedhereinabove. The pump control module 545 uses the number of pulses todetermine the number of revolutions the pump has made, and accordingly,to determine the precise amount of fluid the pump has provided to thebioreactor.

FIG. 6 further illustrates the computer 225 that can be included in autility tower 115 (FIG. 2). In this embodiment, the computer 225includes volatile memory 605, e.g., random access memory, andnon-volatile memory 625, e.g., a hard disk. The computer includes anetwork interface 615, e.g., an Ethernet interface, to communicate withthe controller 120. The computer 225 can run a Windows type-operatingsystem, another operating system that is operationally compatible withthe operating system run on the controller 120 and the control systemsoftware. The computer can also includes a user interface module 630which manages the data input to the control system from, for example, atouchscreen HMI, a wireless device, a keyboard, or a mouse. The userinterface module 630 provides the data as necessary to the controller120 via the network interface 615.

The computer 225 can include a Data History and Trending module 620which can store an electronic history of a process in the memory of thecomputer or use the electronically logged data to show trendinformation. Typically, the computer 225 interacts with the controller120 to electronically record the history of the processes of the one ortwo bioreactors 220, 220′ attached to the utility tower 115 containingthe computer 225. The electronic history can include the temperature,pH, and dissolved oxygen information transmitted from the utility tower115 to the controller 120 during the cell culture process. The historycan also include a detailed log of the events that occurred during aprocess, for example, the amount and type of fluid or gas provided to abioreactor and when it was provided, or the duration of agitationprovided to a bioreactor, the speed of the impeller, and the time theagitation was provided. The data history and trending module 620 furtherallows analysis of the logged history to develop historical trendingwhich can be used for planning subsequent processes.

The computer 225 can also include a batch module 625 that interacts withthe controller 120 via the network interface 615 to allow a sequence ofsteps to be run as without requiring an operator's input at every stepor without reprogramming the control system software. For example, thesequence can include steps to fill a vessel with a specified amount offluid, activating a pump to fill the vessel and turning the pump offwhen the vessel is complete. The batch module 625 allows the operator toemploy the control mechanisms incorporated in the utility tower 115 andthe controller 120 for tasks typically accomplished imprecisely by anoperator. When the batch module 625 is running, the steps executed bythe batch module 625 take priority over preprogrammed steps in thecontrol system software.

The computer 225 can include one or more optional modules (not shown),depending on the desired system configuration. For example, an optionalmodule can include neural network functionality that can model thebehavior of a bioreactor process to help forecast the values of certainprocess measurements and facilitate predictive process control. Thecomputer 225 can also include a module that allows increasedfunctionality of the user interface, for example, allowing the use of avirtual keyboard from a touchscreen HMI.

FIG. 7 illustrates a example configuration for networking multipleutility towers and controllers. In this example, Segment 1 includes tenutility towers 115 a-j, each supporting two bioreactors 220, 220′. Tenutility towers 115 a-j connect to controller 120 by three busses 720,which are, in this example, FOUNDATION™ fieldbus, DeviceNet, andEthernet. Segment 2 includes a similar configuration of utility towers115 k-t that each support two bioreactors 220, 220′, and connect tocontroller 120′ busses 720′, which are also, in this example,FOUNDATION™ fieldbus, DeviceNet, and Ethernet. The controllers 120, 120′are connected by cables 715 which are, for example, FOUNDATION™fieldbus, DeviceNet, and Ethernet. In this way, two controllers 120,120′ can network up to 40 bioreactors. Additional segments containing acontroller, utility towers, and bioreactors can be added to the networkconnections 720 to create an even larger application suite of networkedbenchtop bioreactors. In different embodiments, other types of networkbusses may be used. For example, Profibus can be used instead ofDeviceNet. Additionally, although the network in FIG. 7 is illustratedwith wired connections between the controllers, utility towers and thebioreactors, a suitable wireless technology can also be effectively usedfor any of these connections.

The foregoing description details certain embodiments of the invention.It will be appreciated, however, that no matter how detailed theforegoing appears in text, the invention can be practiced in many ways.As is also stated above, it should be noted that the use of particularterminology when describing certain features or aspects of the inventionshould not be taken to imply that the terminology is being re-definedherein to be restricted to including any specific characteristics of thefeatures or aspects of the invention with which that terminology isassociated. The scope of the invention should therefore be construed inaccordance with the appended claims and any equivalents thereof.

1. (canceled)
 2. A system for generating an electronic history of abioreactor control process, the system comprising: a controllerconfigured to determine control signals to carry out the bioreactorcontrol process, the control signals based at least on informationrelated to a condition in a bioreactor received in the controller over afirst communication network; and a utility tower configured to receivethe control signals from the controller over a second communicationnetwork, the utility tower further configured to change a condition inthe bioreactor, located external to the utility tower, based on thecontrol signals, the utility tower comprising a computer configured torecord an electronic history of conditions occurring in the bioreactorand control actions performed by the utility tower on the bioreactor, amonitoring system that transmits information related to a condition ofthe bioreactor to the controller over the first communication network,and a supply system which supplies a substance to the bioreactor inresponse to a control signal communicated from the controller over thesecond communication network.
 3. The system of claim 2, wherein theelectronic history includes one or more data signals related to acondition of the bioreactor transmitted from the monitoring system tothe controller.
 4. The system of claim 3, wherein the one or more datasignals recorded in the electronic history includes information relatingto a temperature condition of the bioreactor, a pH condition of thebioreactor, a dissolved oxygen (DO) condition of the bioreactor, aglucose condition of the bioreactor, and a concentration of dissolvedoxygen condition of the bioreactor.
 5. The system of claim 2, whereinthe electronic history includes a log of changes in conditions in thebioreactor corresponding to control signals received in the utilitytower from the controller over the second communication network.
 6. Thesystem of claim 2, wherein the electronic history includes informationrelating to an amount of gas added or removed from the bioreactor, atype of gas added or removed from the bioreactor, an amount of liquidsubstance added or removed from the bioreactor, a type of fluid added orremoved from the bioreactor, a duration of agitation of contents of thebioreactor, a speed of an impeller during agitation of contents of thebioreactor, a time the addition or removal of gas started, a time theaddition or removal of gas ended, a time the addition or removal ofliquid substance from the bioreactor started, a time the addition orremoval of liquid substance from the bioreactor ended, a time agitationstarted, and a time agitation ended.
 7. The system of claim 2, whereinthe electronic history is stored in the utility tower.
 8. The system ofclaim 2, wherein the electronic history is stored separate from theutility tower.
 9. The system of claim 2, wherein the computer is furtherconfigured to analyze the recorded electronic history to develophistorical trending information.
 10. The system of claim 9, wherein thebioreactor control process is developed using the historical trendinginformation.
 11. The system of claim 2, wherein the utility towerfurther comprises an agitation system which agitates a solution in thebioreactor in response to a control signal communicated from thecontroller over the second communication network.
 12. A method ofelectronically recording a history of a bioreactor control process, themethod comprising: monitoring a condition in a bioreactor in accordancewith the bioreactor control process; developing, in a utility tower,sensor data related to the condition in the bioreactor, the bioreactorlocated external to the utility tower; sending the sensor data from theutility tower to a controller over a first communication network;determining, in the controller, control signals to carry out thebioreactor control process, the control signals based on at least thesensor data received from the utility tower; sending the control signalsfrom the controller to the utility tower over a second communicationnetwork to change a condition in the bioreactor; supplying a substanceto the bioreactor in response to control signals communicated to theutility tower over the second communication network; and recording anelectronic history of the bioreactor control process performed in thebioreactor.
 13. The method of claim 12, wherein recording an electronichistory includes recording the sensor data transmitted from the utilitytower to the controller over the first communication network.
 14. Themethod of claim 13, wherein the sensor data transmitted from the utilitytower to the controller and recorded in the electronic history includesinformation relating to a temperature condition of the bioreactor, a pHcondition of the bioreactor, a dissolved oxygen (DO) condition of thebioreactor, a glucose condition of the bioreactor, and a concentrationof dissolved oxygen condition of the bioreactor.
 15. The method of claim12, wherein recording an electronic history includes logging changes inconditions in the bioreactor corresponding to control signals receivedin the utility tower from the controller over the second communicationnetwork.
 16. The method of claim 12, wherein the electronic historyincludes information relating to an amount of gas added or removed fromthe bioreactor, a type of gas added or removed from the bioreactor, anamount of liquid substance added or removed from the bioreactor, a typeof fluid added or removed from the bioreactor, a duration of agitationof contents of the bioreactor, a speed of an impeller during agitationof contents of the bioreactor, a time the addition or removal of gasstarted, a time the addition or removal of gas ended, a time theaddition or removal of liquid substance from the bioreactor started, atime the addition or removal of liquid substance from the bioreactorended, a time agitation started, and a time agitation ended.
 17. Themethod of claim 12, further comprising storing the electronic history inthe utility tower.
 18. The method of claim 12, further comprisingstoring the electronic history separate from the utility tower.
 19. Themethod of claim 12, further comprising analyzing the recorded electronichistory and developing historical trending information.
 20. The methodof claim 19, further comprising changing the bioreactor control processusing the historical trending information.
 21. The method of claim 12,further comprising agitation a solution in the bioreactor in response tocontrol signals communicated to the utility tower over the secondcommunication network.